Counterfeit PDE5 Inhibitors Pose Significant Safety Concerns

Wayne J.G. Hellstrom, MD, FACSPresident Elect , International Society of Sexual Medicine

Professor of Urology Chief, Section of Andrology

Tulane University Medical Center

New Orleans, Louisiana

DisclosuresConsultant/Advisory Board Member

Allergan

Anteres

Auxilium

American Medical Systems

Coloplast Endo

Lilly

Neri / Ixchelsis

NIH

Therologix

Absorbent

March,28, 1998

Total Number of PDE5 I Prescriptions (1998 - 2003)

Source: US, IMS Health NPA Plus

Total Rx Market Growth

Source: Verispan VONA

Contraction of PDE 5 inhibitor Market

6% decrease in PDE 5 i prescriptions in 2004-5Was honeymoon period for oral ED meds over?What was big pharma going to do about this?Multiple explanations for this observation

Contraction of PDE5 i market : Reasons

Epidemiologic studies - MMAS, NHSLS, etc.–data over-estimated number of afflicted men & Rx seekers

Cost - single pill relatively expensive

Insurance – removal of Medicaid & HMO coverage

Safety – cardiac concerns, hypotension, NAION, etc.

Decreased interest in female estrogen supplements– diminished desire may reduce demand for male ED drugs

Counterfeit PDE 5 i market – new phenomenon!

Counterfeit Pharmaceuticals

• Scope of the Problem• Online/Internet Sales• Patient Risks Addressing the Problem

Some Facts…..

The WHO estimates 6-10% of products in the worldwide pharmaceutical market are counterfeit

In poor countries, as much as 50% of available drugs are counterfeit or sub-standard

Thousands of deaths globally (Cambodia, Haiti, Nigeria, etc) have been attributed to “fake” medications used to treat malaria, meningitis, etc

Source: WHO

Country and Year

Counterfeiting Problem

Nigeria, 1990 Cough mixture was diluted with a poisonous solvent leading to the deaths of 100 children.

Mexico, 1991 Anti-burn ointment contained sawdust.

Turkey, 1993 A pharmacist is arrested after the active ingredient in ‘drugs’ exported to Africa found to be baking soda.

Niger, 1995 A meningitis drug contained only water.

Haiti, 1996 59 children die after taking a counterfeit syrup for fever.

Kenya, 1998 Anti-malarial drugs were found to be ineffective.

India, 1998 Diethylene glycol poisoning killed at least 30 children.

Brazil, 1998 Ineffective contraceptive pills resulted in unwanted pregnancies.

Malawi, 1999 Africa Health Journal reports an influx of counterfeit drugs into the country.

Italy, 2000 240,000 packs of medicines and 2t of raw materials seized.

China, 2001 The Shenzhen Evening News reports that more than 100,000 people died of fake drugs in 2001.

USA, 2001 Counterfeit Serostim, Neupogen and Nutrupin AQ discovered

India, 2001 Police found 660 kg of fake drugs, 1000 kg of raw materials and boxes bearing the logo of a reputable firm. All of these were discovered in one factory.

Nigeria, 2002 The head of the country’s drug control agency reported that 60% of the drugs were counterfeit, substandard, or expired.

USA, 2002 The FDA reported 3 lots of counterfeit Combivir.

China, 2002 Counterfeit drugs valued at USD 57 million were identified.

USA, 2003 Recall of 200,000 bottles of the anti-cholesterol drug, Lipitor9.

Analyst, 2005, 130, 271-279.

Examples of Counterfeit Drugs

A Growing U.S. ProblemU.S. government estimates that counterfeiting costs the

American economy $200 billion annuallyCounterfeit drug sales $39 billion in 2005 and went up to

$75 billion in 2010 Equals 14% of legitimate pharmaceutical sales

– 13% annual growth rate vs 7.5 percent annual growth for global pharmaceutical commerce

Shift from “mom and pop” operations to highly sophisticated global networks

Fueled by easier access to product via internet

Sources: H.R. 32: Stop Counterfeiting in Manufactured Goods Act; Center for Medicines in the Public Interest

Online pharmaciesThe National Association of Boards of Pharmacy

(NABP) has compiled a ‘Not Recommended Sites’ list, which states that >95% of all online pharmacies are violating US public welfare and safety laws.

Only very few (approximately 30) have NABP Verified Internet Pharmacy Practice Site (VIPPS) accreditation (on-site inspections, prescription mandates and other standard quality requirements).

Of the over 8,000 websites reviewed, more than 85% did not require a valid prescription before shipping drugs to customers.

Liang BA et al. Nature Rev Urol. 2012;9:480-82.

Drug Counterfeiting is Globally Networked

Fill/finishersFill/finishers Flow-throughFlow-through

The Drug Counterfeiting Network Is Globally Integrated

ProducersProducers DestinationDestination

Drugs Smuggled Into the Country

Four Categories of Non-Approved Meds

1. “Generic” Products2. Alternative Formulations3. Herbal Formulations4. Counterfeit Products

1. “Generic” Products

Non-FDA approved versions of branded pharmaceuticals

Contain varying amounts of active ingredients

Often sold at significant price discount to branded products

2. Alternate Formulations

Reformulated to dissolve more quickly

Generally sold as lozenge or gel tab

Make unsupported claims of faster onset

Volume and source of active ingredient unknown

Not FDA approved

3. Herbal Formulations• Purported to be all natural made from plants, herbs or minerals• No scientific evidence demonstrating efficacy• May contain ingredients with potentially dangerous side effects• Marketing claims not rigorously investigated or regulated like

FDA pharmaceuticals• The FDA & FTC have been lax when it

comes to policing these so-called sex supplements

• e.g. Enzyte estimated 2004 sales: $240 million

Source: Center for Science in the Public Interest

20

“Natural” ED Treatments Often Contain Synthetic PDE5-Inhibitors

The field of herbal medicine has gained popularity & these products regarded as harmless due to their “natural” origin

17 commercial formulations of “herbal” or “dietary” supplements marketed for sexual dysfunction were analyzed: 8 of the 17 contained compounds related to synthetic PDE5-inhibitors - sildenafil, tadalafil, vardenafil

The “adulteration” of natural herbal products with ED drugs or analogues is a growing trend & poses a health threat to patients

Source: Balayssac S et al. J Pharm Biomed Anal. 2008.

Herbal remedies from the internet are dangerous

Study safety & reliability of internet sites selling “herbal Viagra” “Google” search engine: 160,000 hits assessed

– 88% outlined effectiveness of drugs

– 70% stated drug ingredients –commonest: yohimbine, ginseng and gingko biloba

– 21% gave drug side effects e.g. bleeding and cardiac arrhythmia with gingko

– 21% had medically trained personnel providing information

– 18% had referenced information

None of sites met Code of Conduct requirements set by Health on the Net Foundation (body that accredits medical websites)

Internet sites selling herbal ED remedies unsafe and unreliable

Thurairaja et al, J Urol 2004: 171, 1191A

4. Counterfeit Drug Production

WHO definition: deliberately and fraudulently mislabeled with respect to identity and source

The composition of counterfeit drugs is highly variable– Sub-potent– Supra-potent– Mixed with other active ingredients or unknown substances– Similar to genuine drug

Production facilities for counterfeit drugs are frequently unsterile and in uncontrolled environments

Authentic Products Are Manufactured in Regulated and Inspected Facilities

Counterfeiters’ manufacturing facilities are frequently unsterile

Storage Facilities Inadequate

Counterfeit Viagra Manufactured in Substandard FacilitiesCement mixer used to dye tablets in Egypt

Bucket used to mix ingredients in China

Counterfeit Viagra Factory in Thailand

Tableting Machine in South America

Counterfeiters Labeling Equipment are Now More Sophisticated

An Important Issue for Sexual Health MD’s• Sexual health products among the most counterfeited

• In 2004, Pfizer seized 10.1 million counterfeit Viagra tablets

• 7 times all other Pfizer products combined

• Additional 1,499kg of bulk sildenafil seized (~28 million tablets)

Sources: WHO

Prime Target of Counterfeiters

Reasons for buying online PDE5i’s:– High cost of prescription medication– Embarrassment associated with underlying condition

Most counterfeit PDE5 inhibitors enter the United States drug market via fraudulent websites accessed easily on the internet.

“The internet is just the wild, wild west”- Bryon A. Liang

Online Sales of Non-Approved “VIAGRA” Approximately 2,700 websites selling Viagra-like products12.9 million visitors per monthEstimated 2.3 million tablets purchased per month

Websites Monthly Sales (000s)

Source: Cyveillance, Inc.

“Real” Viagra Generic Alt. Form. Herbal

33EAASM “Counterfeiting Superhighway” Research (European Alliance for Access to Safe Medicines)

Source: EAASM. The Counterfeiting Superhighway. 2008. Available at: www.eaasm.eu/Media_centre/EAASM_reports. Accessed: January 15, 2009.

• Identified and assessed >100 online pharmacies• 3 phases: finding and inspecting pharmacies, purchasing medicines

online, unwrapping and expert analysis

Is there a named, verifiable pharmacist?

Does the pharmacy physically exist?

Is the website violating intellectual property?

Yes6.2%

No93.8%

Yes15.5%

No84.5%

Yes78.8%

No22.2%

Is a prescription required for prescription-only

medicines?

Yes9.7%

No90.3%

34

Seized Sildenafil Counterfeits and Imitations in Europe

Source: Data on File. Pfizer, Inc.

444,576

2,114,937 1,730,632

2,024,766

1,499,258 2,125,671

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000

3,500,000

4,000,000

2006 2007 2008

ImitationsCounterfeits

Pfizer analyzed 2383 samples seized by authorities worldwide for suspicion of being counterfeit Viagra

626 (26%) were seized in the United Kingdom.

By spectral analysis, only 85 (14%) samples were authentic.

320 (51%) were ordered via the Internet; 264 (83%) of these samples were counterfeit.

Jackson G et al. Int J Clin Pract. 2012;66:2141-250

Seized Sildenafil Counterfeits and Imitations in the UK

Sildenafil mg/unitP

erce

ntag

e of

sam

ples

Risks to Patients• Financial Risks

• Lost money• Orders often unfulfilled• Shipping & consultation fees may offset advertised savings

• Identity theft• Limited legal recourse

• Safety Risks• No prescription required

• Inadequate review by online doctors• Risk of drug-drug interactions

• Product quality• Incorrect medicine • Expired medications• Little or no active ingredients• Improper storing/distribution• Contaminants• Lack of package insert

Source: Prevention, February 2004

• Aim: Evaluate men who obtain PDE5 inhibitors without healthcare professional (HCP) interaction

• Methods: Web-based observational study in UK, Germany, and Italy • Results: Of 11,899 participants; 1,252 (10.5%) reported PDE5

inhibitor use in last six months; 403 (32.3%) without HCP interaction; 65% had ED by IIEF

Schnetzler G et al. J Sex Med 2010;7:1237-46.

1/3 of Men Obtaining Treatment for ED are Currently Outside the Healthcare System (HCS)

Source: Banks I et al. Presented at: Joint Congress of the European and International Societies for Sexual Medicine (ESSM/ISSM); December 7-11, 2008; Brussels, Belgium. Poster MP-026.

Patients Outside the HCS by Age (%)

40.7

29.0

14.6

0

20

40

60

80

100

18-40Years

41-60Years

≥61Years

30.6

48.4

15.3

27.6

0

20

40

60

80

100

Total United Kingdom

France Germany

Patients Outside the HCS by Country (%)

43.6%

P<0.0001 vs UK

P<0.0001 vs UK

P<0.0001 ≥61 vs 18-40

Men were considered outside the HCS if they had no contact with a healthcare professional todiagnose, prescribe, or provide treatment for ED. Treatment was outside the HCS if it wasacquired without prescription via the Internet, a mail-order pharmacy, or from afriend/acquaintance or partner.

Men who bypassed the healthcare system were FOUR times more likely to purchase an imitation PDE5i

Source: Banks I et al. Presented at: Joint Congress of the European and International Societies for Sexual Medicine (ESSM/ISSM); December 7-11, 2008; Brussels, Belgium. Poster MP-026.

Purchases of Imitation PDE5-Inhibitors by Men Who Interacted Within the HCS vs Those Who Did Not Interact

Within the HCS

(%)

7%7%

93%93%

28%28%

72%72%

0

20

40

60

80

100

Within HCS Outside HCS

ImitationsMarketed

40

72% of men who bypassed the healthcare system to obtain treatment had ED

*ED severity was determined with the Massachusetts Male Aging Study question.

Source: Banks I et al. Presented at: 11th Congress of the European Society for Sexual Medicine; December 7-11, 2008; Brussels, Belgium. Poster 2143.

(%)

Severity of ED*

72%

43%

25%4%

0

15

30

45

60

75

90

Outside HCS

MildModerateSevere

PDE5 inhibitor use without HCP interaction is a public health concern:

1. Men expose themselves to risk of unapproved generics and unnecessary risk of counterfeit medications

2. These future patients miss the opportunity to receive information on correct product use and contraindications

3. These men bypass opportunity to receive appropriate health information and medical follow-up for unrecognized CV disease. Hence, delay in diagnosis of cardiac risk factor e.g. HTN, DM, hyperlipidemia, etc

Schnetzler G et al. J Sex Med 2010;7:1237-46.

Reasons Men with ED May Not Consult a Healthcare Professional

GermanyUK Belgium France Spain Italy

0

20

40

60

80

100

%

72.3 62.9 79.8 62.9 79.0 67.4

% Total Respondents Per Country Who DID NOT Consult a Physician

Telephone survey (2000–2001) conducted worldwide in people aged 40–80 years (men, n = 4977; women, n = 5023).

Source: Nicolosi A et al. World J Urol. 2006;24:423-428.

Lack of perception of problems

Thinks issue is not a medical problem

Embarrassment

Problem with access to or affordability of

medical care

Reasons For Not Consulting a

Physician

1,144 men who reported PDE5i use within the past year

22.0% of men obtained PDE5i via the Internet.

Counterfeit drugs survey in Japan and Thailand revealed that 55.4% of the PDE5i obtained via the Internet are counterfeits

Lower awareness of better general health, lower awareness of ED, lower rate of alcohol intake, fear of HCP interview to obtain PDE5i were independent prognostic factors for purchase via the internet

Kimura M et. J Sex Med. 2012. 9;1649-1652Sasaki H et al. Jpn J Sex Med. 2011;25:19–28)

Reasons for Exponential Growth in Drug Fraud and Counterfeiting:

1. Increase in price of prescription medications (PDE5 I’s)

2. Growth of unregulated internet pharmacies “The internet is the wild, wild west”

3. Entry of organized crime syndicates

$1,000 DOWN – returns $20,000 on heroin$1,000 DOWN – returns $450,000 on fake Viagra

Legal repercussions not as severe for drug counterfeiting as it is for narcotic charges

Methods to discriminate PDE5 I from counterfeited drugs

Chromatography

– Thin layer chromatography (TLC), High pressure liquid chromatography with ultraviolet detection (HPLC-UV), Liquid chromatography with mass spectrometric detection (LC-MS), LC-diode array detection (DAD), Ultra-high-performance liquid chromatography-UV-method (UHPLC)

X-ray fluoroscopy spectrometry

Raman spectroscopy

Near infrared spectroscopy

Atmospheric solid analysis probe (ASAP)

Deconinck E et al. Talanta. 2012;100:123-133Lebel P et al. Journal of Chromatography A. 2014;1343:143-151

Sacre PY et al. Journal of Chromatography A. 2011;1218:6439-6447

Between January 1 and May 26, 2008, a total of 150 non-diabetic patients were admitted to 5 hospitals in Singapore with severe hypoglycemia– All patients except one were male

– Ages ranged from 19 to 97 years (median, 51)

– 7 patients comatose caused by severe & prolonged hypoglycemia

– Four subsequently died

Glyburide was detected in blood or urine samples obtained from 127 of these patients (85%).

Glyburide is one of the most widely prescribed oral sulfonylurea drug used to treat type II diabetes

Kao et al, NEJM 2009;360:734-735.

Counterfeiting: a case study

HPLC: high‐performance liquid chromatography

HPLC analysis of counterfeit drug (A) and Pfizer manufactured drug (B)

Kao et al, NEJM 2009;360:734-735.

On specific questioning, 45 patients (30%) admitted ingesting illegal sex-enhancement drugs before the onset of hypoglycemia

Samples of the counterfeit drugs were obtained from patients and from drugs seized in police raids

The counterfeit drugs were sold as Viagra, Cialis, and 3 herbal preparations for ED (Power 1 Walnut, Santi Bovine Penis Erecting Capsule, and Zhong Hua Niu Bian)

Four drugs were analyzed by HPLC

– In addition to containing sildenafil, some of the counterfeit drugs contained tadalafil and sibutramine

Counterfeiting: a case study

Kao et al, NEJM 2009;360:734-735.

Campbell N et al. J Sex Med. 2012;9:2943-2951

Campbell N et al. J Sex Med. 2012;9:2943-2951

Infrared Spectroscopy

Raman Spectroscopy

UltravioletSpectroscopy77% counterfeit, 18% authentic, and 5% illegal

97 samples claiming to contain sildenafil, tadalafil, or vardenafil seized or purchased from online pharmacies by Italian authorities

All the samples purchased online were easily obtained without a physician’s prescription

Analyzed by visual inspection, liquid chromatography, Infrared Spectroscopy, Differential Scanning Calorimetry, and Thermo-Gravimetry

Gaudiano MC et al. J Sex Med. 2012;9:2130-2137

Gaudiano MC et al. J Sex Med. 2012;9:2130-2137

Composition of illegal substances

OOS=Out of specification

Original 7%Illegal 54%Counterfeit 24%

Counterfeit Medications:What can WE do about it?

Healthcare Professionals

Healthcare Professionals

Regulatory AuthoritiesRegulatory Authorities

PatientsPatients

Pharmaceutical Companies

Pharmaceutical Companies

Efforts to Control Counterfeit Distribution

• PDE5 inhibitor Companies• --Working with regulatory and law enforcement authorities

• --Distinctive Packaging

• --Holographic Security Foil

• --2D Barcode

• -- Radio Frequency Identification (RFID) tags

• World Health Organization (WHO)1

• In 2006, created a global coalition of stakeholders called IMPACT (International Medical Products Anti-Counterfeiting Taskforce), which aims to build coordinated networks across and between countries in order to halt the production, trading, and selling of fake medicines around the globe

Source: 1. WHO Available at: http://www.who.int/impact/impact_q-a/en/index.html. Accessed September 16, 2009.

Radiofrequency identification tags

The unfunded cost of implementation of FDA e-pedigree mandates in the USA have been estimated to range from $84,000 for individual pharmacies to $1.3billion for large-chain pharmacies and may present significant barriers to RFID adoption

Paxton M. Clin Pharmacol Ther. 2011;89:316-319

FDA has significantly increased the number of counterfeit drug cases it has initiated and prosecuted

Aimed at intercepting product before entering the physical drug supply chain

FDA Enforcement

Source: FDA

Counterfeit drug cases opened by FDA per year

Suggested trilateral working group

Source: Mackey TK et al. BMC Medicine. 2013;11:233-43.

Educating Consumers on the Risks of Counterfeit Meds

FDA launched significant public education campaign– Magazine PSAs reaching 4.5 million readers

– 4.6 million education leaflets distributed by retail pharmacies

– News articles reaching 9.5 million consumers

– Consumer website: www.fda.gov/counterfeit

– Pharmacist education program in development

PDE5 I companies have educated potential ED patients on risks of buying non-FDA approved products

– Sponsored search engine results educate consumers

– e.g.Viagra.com features extensive information on risks of fake Viagra

• Be familiar with size, shape, color, taste, and odor of medications

• Be suspicious of drugs with an unusually low price• “If the price is too good to be true, it probably isn’t!”

• Be suspicious of online pharmacies and/or any vendor that does not provide a physical address & telephone landline

• Look for evidence of a removed or switched product label and/or subtle changes in packaging, including alterations in the expiration date

• Report new side effects to a pharmacist and prescribing health professional, especially unexpected side effects

Preventing counterfeiting:What patients can do

Gaudiano MC et al. J Sex Med. 2012;9:2130-2137

What You the Physician Can Do Continue to advocate treatment of sexual health conditions

– Support efforts to maintain consumer access to sexual health medicines

– Encourage non-specialists to probe for sexual concerns

Educate patients on the risks of counterfeit & other non-FDA approved products

Remind them to only purchase from a VIPPS-certified pharmacy if they want to fill their prescription online

Report any suspected cases of counterfeit medicines to FDA– http://www.fda.gov/medwatch

Summary: What can be done about Counterfeit PDE5 Inhibitors

Recognize that this is truly an international problem Implement a worldwide consensus on what is

counterfeit Increase penalties and finesEducate physicians on the real dangers of counterfeit

drugs and the need to take a stand against themInform patients of the risks of purchasing medications

from internet pharmacies

63

Pharmacological risks posed by counterfeit PDE5-inhibitors are significant

Direct Risks

Presence of unknown pharmaceutically active ingredients and/or impurities may lead to undesirable and serious side effects or even death

Dosage variability and dosage mislabeling may lead to accidental overdoseIncorrect or incomplete descriptions of product composition create substantial risk for drug-drug interactions

Minimal or incorrect guidance about contraindications may lead to serious side effects

Indirect Risks

Unsupervised use of PDE5-inhibitors, particularly by men with ED and common comorbid conditions (e.g., hypertension, dyslipidemia, diabetes) may incur

— Significant risk of morbidityor mortality

— Missed opportunity to address underlying conditions

No basis for determination of drug efficacy or guidance for future use

Addressing side effects caused by an unknown product is difficult and may be dangerous

Sources: 1. Blok-Tip L et al. RIVM Report. 2005. Report number 267041001. 2. Dorsey PH, Hellstrom WJG. Medscape Urol (Posted 12/11/2007).

BP Oil Spill 2010

ISSM Policy Statement #1

Counterfeit drugs are a significant threat to public health. In most studies of the content of counterfeit drugs, the counterfeit product does not contain the amount or type of drug claimed by the product packaging. In many cases, the counterfeit drug contains pharmacological substances not named by the product’s packaging, some of which are illegal and dangerous. Deaths and serious illnesses have been caused by the presence of unnamed pharmacological products in counterfeit drug products. It is impossible for a patient or a healthcare practitioner to know whether or not the stated content of a counterfeit drug is accurate or whether dangerous substances have been added to a product.